β-Ionone suppresses colorectal tumorigenesis by activating OR51E2, a potential tumor suppressor

Background: Olfactory receptors (ORs) are present in non-olfactory tissues and contribute to diverse biological roles beyond smell perception. Among them, OR51E2 has been associated with cancer biology, and its activator, β-ionone, a natural terpenoid, is known to have anticancer effects. Purpose: This study aimed to clarify the tumor-suppressive role of OR51E2 in colorectal cancer (CRC), unravel the regulatory mechanism underlying its downregulation, and evaluate the therapeutic potential of β-ionone, an OR51E2 ligand, in CRC progression. Study design and methods: OR51E2 expression was analyzed in human CRC tissues, matched adjacent normal tissues, and cell lines. The involvement of N⁶-methyladenosine (m⁶A) modification of OR51E2 mRNA stability was examined using METTL3/14 and YTHDF1/2/3 knockdown experiments. β-Ionone-mediated effects on intracellular calcium signaling, cell proliferation, migration, and apoptosis were evaluated in an OR51E2-dependent manner. The therapeutic efficacy of β-ionone was further evaluated in vivo using a xenograft model in nude mice. Results: OR51E2 mRNA expression and immunoreactivity were significantly reduced in CRC cells and tissues due to decreased mRNA stability. Knockdown of METTL3/14 or YTHDF1/2/3 increased OR51E2 mRNA and protein expression and inhibited CRC cell proliferation. Treatment with STM2457, an METTL3 inhibitor, restored OR51E2 expression and suppressed CRC cell proliferation. β-Ionone, a ligand of OR51E2, increased intracellular calcium levels, decreased MEK/ERK phosphorylation, and inhibited CRC cell proliferation while inducing apoptosis. These effects were abolished in OR51E2 knockdown cells. In a xenograft model, β-ionone administration (5 and 10 mg/kg body weight) significantly reduced tumor growth. Conclusion: This study identifies m⁶A modification as a critical mechanism underlying the downregulation of OR51E2 in CRC. Activation of OR51E2 by β-ionone suppresses CRC cell proliferation and induces apoptosis by elevating intracellular calcium levels, which inhibits the MEK-ERK pathway. These findings highlight OR51E2 as a potential therapeutic target and suggest that β-ionone or m⁶A inhibition may represent novel strategies for CRC treatment.